In U.S. Pat. No. 4,804,663 there are described 1,2-benzisoxazol-3-yl and 1,2-benzisothiazol-3-yl derivatives having antipsychotic and antiserotonin activity. In EP-A-0,378,255 there are described 4-aminopyrimidinone derivatives as antagonists of the neurotransmitters serotonin and histamine. In JP-A-2-63911 there are described benzothiophene- and benzofuranderivatives as 5-HT2 receptor antagonists useful for treating ischaemic heart disease, cerebrovascular disease, depression or schizophrenia. The present compounds differ structurally and show a different pharmacological profile.
The invention is concerned with novel compounds of the formula 
the pharmaceutically acceptable acid addition salts thereof and the stereochemically isomeric forms thereof, wherein
X is oxygen or sulphur;
R1 is hydrogen or halo;
R2 is hydrogen, C1-4alkyl, phenylmethyl or halophenylmethyl;
Alk is C1-4alkanediyl;
xe2x80x94Zxe2x80x94Axe2x80x94 is a bivalent radical selected from the group consisting of xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94C(xe2x95x90CHR3)xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94CHR4xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHR4xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHR4xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94;
wherein in said bivalent radicals one hydrogen may be replaced by C1-4alkyl;
R3 is phenyl or halophenyl; and
each R4 independently represents hydrogen, hydroxy, phenylmethyl or halophenylmethyl.
In the foregoing and hereinafter C1-4alkanediyl defines bivalent straight and branched chain alkanediyl radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the branched isomers thereof; halo is generic to fluoro, chloro, bromo and iodo; C1-4alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1,1-dimethylethyl, 1-methyl-propyl, 2-methylpropyl and the like; and halophenylmethyl defines fluorophenylmethyl, chlorophenylmethyl, bromophenylmethyl, iodophenylmethyl and the like.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have either the R- or the S-configuration; substituents on bivalent cyclic saturated hydrocarbon radicals may have either the cis- or trans-configuration and radicals or moieties containing double bonds may have the E- or Z-configuration. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with appropriate acids such as, for example, inorganic acids, such as hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, hydroxyacetic, propanoic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form. The term acid addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
R1 is suitably hydrogen or fluoro;
R2 is suitably phenylmethyl or C1-4alkyl, preferably methyl;
Alk is suitably C2-3alkanediyl, preferably 1,2-ethanediyl or 1,3-propanediyl;
R3 is suitably phenyl or fluorophenyl, especially 4-fluorophenyl;
R4 is suitably hydrogen, hydroxy or halophenylmethyl, especially fluorophenylmethyl.
Particular compounds are those compounds of formula (I), wherein xe2x80x94Zxe2x80x94Axe2x80x94 is a bivalent radical of formula xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Sxe2x80x94CHxe2x80x94C(CH3)xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, or xe2x80x94CHxe2x95x90C(CH3)xe2x80x94Oxe2x80x94.
Also particular compounds are those compounds of formula (I), wherein xe2x80x94Zxe2x80x94Axe2x80x94 is a bivalent radical of formula xe2x80x94CHR4xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHR4xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CHR4xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, wherein R4 is hydrogen, hydroxy or halophenylmethyl, especially fluorophenylmethyl; or xe2x80x94C(xe2x95x90CHR3)xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, wherein R3 is phenyl or halophenyl, particularly 4-halophenyl, especially fluorophenyl, preferably 4-fluorophenyl.
A first group of particularly interesting compounds are those compounds, wherein Alk is 1,2-ethanediyl or 1,3-propanediyl, R4 is hydrogen and X is oxygen or sulfur, preferably oxygen.
Another group of particularly interesting compounds are those compounds, wherein xe2x80x94Zxe2x80x94Axe2x80x94 is a bivalent radical of formula xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CHxe2x95x90C(CH3)xe2x80x94Oxe2x80x94.
Preferred compounds are:
6-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;
3-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one;
6-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo-[3,2-a]pyrimidin-5-one;
6-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidilyl]ethyl]-2,5-dimethyl-7H-isoxazolo-[2,3-a]pyrimidin-7-one;
6-[2-[4-(3-benzo[b]thienyl)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;
3-[2-[4-(3-benzo[b]thienyl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;
3-[2-[4-(3-benzo[b]thienyl)-1-piperidinyl]ethyl]-2,9-dimethyl-4H-pyrido-[1,2-a]pyrimidin-4-one;
3-[3-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]propyl]-2,9-dimethyl-4H-pyrido-[1,2-a]pyrimidin-4-one;
3-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]ethyl]-2-(phenylmethyl)-4H-pyrido-[1,2-a]pyrimidin-4-one, the stereochemically isomeric forms and the pharmaceutically acceptable acid addition salts thereof.
Most preferred compounds are:
3-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one,
6-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo-[3,2-a]pyrimidin-5-one and the pharmaceutically acceptable acid-addition salts thereof.
The compounds of formula (I) can generally be prepared by N-alkylating an intermediate of formula (II) with an intermediate of formula (III). In formula (III) and the formulae hereinafter, W1 represents a reactive leaving group such as, for example, halo, e.g. chloro, bromo or iodo, or a sulfonyloxygroup, e.g. methanesulfonyloxy, 4-methylbenzenesulphonyloxy and the like. 
The reaction of (II) with (III) can conveniently be conducted in a reaction-inert organic solvent such as, for example, an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene and the like; a lower alkanol, e.g. methanol, ethanol, 1-butanol and the like; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone and the like; an ether, e.g. 1,4-dioxane, 1,1xe2x80x2-oxybisethane, tetrahydrofuran and the like; N,N-dimethylformamide, N,N-dimethylacetamide, nitrobenzene, 1-methyl-2-pyrrolidinone and the like. The addition of an appropriate base such as, for example, an alkali or an earth alkaline metal carbonate, hydrogen carbonate, hydroxide, alkoxide or hydride, e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium hydride and the like, or an organic base such as, for example, a tertiairy amine, e.g. N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine and the like, may be useful to pick up the acid which is liberated during the course of the reaction. In some circumstances the addition of a iodide salt, preferably an alkali metal iodide, is appropriate. Somewhat elevated temperatures may enhance the rate of the reaction.
The compounds of formula (I), can also be prepared following art-known cyclizing procedures for preparing pyrimidin-4-ones such as, for example, by reacting an amine of formula (IV) with a xcex2-dicarbonyl derivative of formula (V) or by cyclizing a reagent of formula (VI) with an enamine of formula (VII). In formula (V) and in the formulae hereinafter each W2 independently represents an appropriate leaving group such as, for example, hydroxy, halo, C1-4alkyloxy, C1-4alkylcarbonyloxy, amino, mono- or di(C1-4alkyl)amino. 
Said cyclization reactions may generally be carried out by stirring the reactants, optionally in the presence of a suitable reaction-inert solvent such as, for example, an aliphatic, alicyclic or aromatic hydrocarbon, e.g. hexane, cyclohexane or benzene and the like; or pyridine, N,N-dimethylformamide and the like dipolar aprotic solvents. Elevated temperatures may be appropriate to enhance the reaction rate; more in particular it may be advantageous to carry out the reaction at the reflux temperature of the reaction mixture.
Following the same procedure the compounds of formula (I) can also be prepared by cyclizing an intermediate of formula (VII) with a reagent of formula (VIII). 
The compounds of formula (I) wherein Zxe2x80x94A is a bivalent radical xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 and wherein in said bivalent radicals one hydrogen may be replaced by C1-4alkyl, said compounds being represented by the formula (I-a), can also be prepared by cyclizing a 2-mercaptopyrimidinone of formula (IX) with a reagent of formula (X), wherein n is 2 or 3 and wherein one hydrogen may be replaced by C1-4alkyl. 
The compounds of formula (I) wherein Zxe2x80x94A is a bivalent radical of formula xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94, wherein one hydrogen may be replaced by C1-4alkyl, said compounds being represented by the formula (I-b), can be prepared by cyclizing a 2-mercapto-pyrimidinone of formula (IX) with a reagent of formula (XI) wherein one hydrogen atom may be replaced by C1-4alkyl. 
Said cyclization reactions for preparing the compounds of formulae (I-a) and (I-b) may generally be carried out by stirring the reactants, if desired, in the presence of a suitable reaction-inert solvent such as, for example, an aliphatic, alicyclic or aromatic hydrocarbon, e.g. hexane, cyclohexane or benzene and the like; or pyridine, N,N-dimethylfornamide and the like dipolar aprotic solvents. Elevated temperatures may be appropriate to enhance the reaction-rate, more in particular it may be preferred to carry out the reaction at the reflux temperature of the reaction mixture.
The compounds of formula (I) may also be converted into each other using art-known functional group transformations. For example, compounds of formula (I), wherein R1 is hydrogen may be converted into compounds of formula (I) wherein R1 is halo using art-known halogenation techniques.
A number of intermediates and starting materials in the foregoing preparations are known compounds which may be prepared according to art-known methodologies of preparing said or similar compounds. The intermediates of formula (III) and their preparations are described in U.S. Pat. No. 4,804,663 and in the references cited therein.
The intermediates of formula (II) wherein X is oxygen, said intermediates being represented by formula (II-a), can be prepared by cyclizing an aldehyde of formula (XII) and deprotecting the intermediate of formula (XIII). In formula (XII) and the formulae hereinunder P represents a protective group such as for example C1-6alkylcarbonyl and W3 represent a reactive leaving group such as, for example, halo, e.g. fluoro, chloro, bromo, iodo. 
Said cyclization may conveniently be conducted by treating the aldehyde of formula (XII) with an appropriate base in an reaction-inert organic solvent such as, for example, an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene and the like, an ether, e.g. 1,4-dioxane, 1,1xe2x80x2-oxybisethane, tetrahydrofuran and like; a dipolar aprotic solvent, such as, for example N,N-dimethylformamide, N N-dimethylacetamide and the like. Appropriate bases are for example alkali or earth alkaline metal carbonate, hydrogen carbonate, hydroxide, alkoxide, hydride, e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium hydride and the like, or an organic base such as a tertiary amine, e.g. N,N-ethylethanamine, N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine and the like.
The intermediate aldehyde of formula (XII) can be prepared by reacting an epoxide of formula (XIV) with an acid, such as, for example, a mineral acid, e.g. perchloric acid, sulphuric acid and the like; a Lewis acid, e.g. borontrifluoride, magnesiumdibromide, aluminiumtrichloride and the like in an appropriate solvent. 
Depending upon the nature of the acid, appropriate solvents are water; alkanols, e.g. methanol, ethanol and the like; aromatic hydrocarbons, e.g. benzene, methylbenzene, dimethylbenzene and the like; ethers, e.g. 1,1xe2x80x2oxybisethane, tetrahydrofuran and the like; halogenated hydrocarbons, e.g. dichloromethane, trichloromethane and the like. Stirring and elevated temperatures may enhance the rate of the reaction.
The epoxides of formula (XIV) can be obtained by stirring a ketone of formula (XV) with a sulphur ylide, such as dimethyloxosulfonium methylide or dimethylsulfonium methylide in an appropriate solvent, such as, for example, an ether, e.g. 1,1xe2x80x2-oxybisethane, tetrahydrofuran, 2,2xe2x80x2-oxybispropane and the like; a dipolar aprotic solvent, e.g. dimethylsulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide and the like. 
The ketones of formula (XV) can be prepared by a Friedel-Crafts acylation of piperidines of formula (XVI) wherein W4 is a reactive leaving group such as for example hydroxy, halo, C1-4carbonyloxy and the like, with benzenederivative of formula (XVII). Said Friedel-Crafts acylation can be performed by stirring the reactants in the presence of an acid in a reaction-inert solvent, such as for example, an ether, e.g. 1,1xe2x80x2-oxybisethane, 2,2xe2x80x2oxybispropane, tetrahydrofuran, dioxane and the like, a halogenated hydrocarbon, e.g. dichloromethane, trichloromethane and the like. Suitable acids are mineral acids such as sulphuric acid, phosphoric acid, phosphorous pentoxide and the like, Lewis acids, e.g. aluminiumtrichloride, ferric chloride, zinc chloride and the like.
The compounds of formula (I) and the pharmaceutically acceptable acid addition salts have useful pharmacological properties. For example, the compounds of formula (I) possess anti-dopamine activity and show good affinity for several serotonin receptors, especially 5HT1A. Said compounds can also inhibit neuronal serotonin reuptake. Furthermore the compounds of formula (I) antagonize the action of reserpine (cfr. Example 3). Due to their pharmacological activities, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used in the treatment of psychotic diseases and in the treatment of a variety of complaints in which serotonin is of predominant importance. The present compounds may block serotonin-induced contractions of bronchial tissues and of blood vessels, arteries as well as veins. Particularly in view of their reserpine-antagonizing activity the compounds of formula (I) also have useful properties as anti-depressants, anxiolytics, antitremor agents and show activity against obsessive compulsive disorders, such as anorexia, bulimia and addiction, e.g. alcohol abuse.
The compounds of the present invention therefore may be used as medicines against above-mentioned conditions. Said use as a medicine or method of treatment comprises the systemic administration to patients of an amount effective to combat the conditions such as depression, anxiety, obsessive compulsive disorders, tremor and the like.
The subject compounds may be formulated into various pharmaceutical forms for administration purposes. Said pharmaceutical forms or compositions are deemed novel and consequently constitute another aspect of the present invention. Also the preparation of said compositions constitutes a further aspect of the present invention. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employee In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdernal patch, as a spot-on or as an ointment. Acid addition salts of (I) due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
In view of the usefulness of the subject compounds in the treatment of neurotransmitter mediated diseases it is evident that the present invention provides a method of treating warm-blooded animals suffering from such diseases, said method comprising the systemic administration of a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutical carrier. Those of skill in the treatment of diseases associated with neurotransmitters could easily determine the effective amount. In general it is contemplated that an effective amount would be from 0.01 mg/kg to 4 mg/kg body weight, preferably from 0.04 mg/kg to 2 mg/kg body weight.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore guidelines only and are not intended to limit the scope or use of the invention to any extent.